Ischemic Cell Damage

Ischemic cell damage is the injury of a cell arising from reduced blood flow. The process involves hypoxia from interrupted blood supply, lack of nutrients, and accumulation of toxic metabolites. Damage to the cell can be reversible (function returns when blood flow resumes) or irreversible (the reversibility threshold has passed). While blood flow can be restored and allow cell recovery, reperfusion injury is possible in previously ischemic tissues. By producing calcium overload, oxidative stress and inflammatory mechanisms involving immune cells, cytokines, and the complement system, reperfusion can also lead to cell death (often by necrosis). Susceptibility to ischemia is affected by different factors, which include high metabolic activity, the presence of collateral circulation, watershed areas, and the magnitude of ischemia. The organ most susceptible to ischemia is the brain. Other susceptible organs include the heart, kidneys, liver, and the large intestine.

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Overview

Definition

Ischemic cell injury is damage arising from a decrease in blood flow, which leads to hypoxia, lack of nutrients, and accumulation of toxic metabolites.

  • Hypoxia: decreased oxygen supply (blood flow often maintained)
  • Reperfusion injury: tissue damage from restoration of blood supply after an ischemic event

Cell injury

In cell injury, either the cells either cannot adapt or the maximum adaptive response to physiologic or pathologic stimuli is exceeded.

Ischemia and reperfusion injury are 2 causes of stimuli leading to cell injury and death.

Other injurious stimuli include physical causes such as trauma or radiation, chemicals, loss of critical nutrients, and mutations.

Stages of cell injury and death:

  • Reversible injury: damage to the cell → ATP depletion → leakage of ions → ion imbalance → cell and organelle swelling
  • Irreversible injury:
    • The reversibility threshold for the cell has passed and cellular function cannot be restored.
    • The cell is committed to cell death.
  • Cell death (via processes such as necrosis and apoptosis)

Cell death

Necrosis (most common cause):

  • Nonphysiological
  • Uncontrolled cell death after irreversible injury
  • Membrane damage causes an influx of calcium → organelle swelling → digestive enzyme release, which leads to:
    • Pyknosis: nuclear shrinkage
    • Karyorrhexis: nuclear fragmentation 
    • Karyolysis: nuclear fading

Apoptosis (small percentage):

  • Programmed cell death
  • Activated by the release of proapoptotic molecules from the mitochondria (physiologic response)
  • Extrinsic pathways: 
    • Fas (CD95) → Fas ligand (FasL)
    • Tumor necrosis factor (TNF)-α → TNF receptor 1 (TNR1)
  • Intrinsic pathway (mitochondrial pathway):
    • DNA damage → p53 activated → cell cycle arrest → p53 activates apoptosis 
    • ↑ Proapoptotic proteins (e.g., BAK and BAX), ↓ antiapoptotic proteins (e.g., Bcl-2) → mitochondria release cytochrome c
    • Cytochrome c binds apoptosis protease-activating factor (APAF)-1 → activation of caspase and endonuclease
  • Perforin/granzyme pathway: 
    • Utilized by cytotoxic T cells and natural killer cells
    • Perforin pores are created in target cells, which allow entry of caspase-like granzyme.

Dead cells are replaced by phospholipids and myelin figures, resulting in clarification or phagocytosis by macrophages.

Ischemic Injury

Ischemia

Injury from ischemia can be due to:

  • ↓ Supply of blood: mechanical arterial obstruction (most common):
    • Atherosclerosis: plaque building up in arterial walls
    • Thromboembolism: blockage of a blood vessel by a clot dislodged from another source in the body
  • ↓ Venous drainage of blood: venous flow stops:
    • Deep vein thrombosis: a blood clot in the deep veins
    • Peripheral venous disease: progressive stenosis of veins
  • Shock:
    • Life-threatening disorder due to lack of blood flow
    • 4 main types:
      • Hypovolemic: ↓ intravascular volume (e.g., blood loss)
      • Cardiogenic: ↓ left ventricular function (e.g., congestive heart failure)
      • Distributive: septic (from sepsis), neurogenic (e.g., spinal cord injury), or anaphylactic
      • Obstructive: lack of cardiac outflow (e.g., tension pneumothorax/tamponade or pulmonary embolism)

Mechanism of injury

  • ↓ Oxygen availability (aerobic metabolism is interrupted) → reduced ATP production → failure of energy-dependent systems:
    • Plasma membrane +Na+-K+ pump (Na⁺, K⁺-ATPase) fails → sodium enters the cell → cell swells
    • Anaerobic metabolism compensates for the ATP loss → depleted glycogen → ↑ lactic acid → ↓ intracellular pH → impaired enzymes
    • Impaired enzymes lead to reduced protein synthesis → detachment of ribosomes 
  • Microscopic changes:
    • Loss of microvilli and formation of “blebs” in the cytoplasm and on the cell membrane
    • Cell and organelles swell
  • Cells start to lose functionality.
  • ↑ Intracellular concentrations of water, sodium, and chloride, but potassium
  • All changes are reversible if perfusion and oxygenation are restored. 
  • If ischemia persists, the tissue succumbs to irreversible injury and death.

Reperfusion Injury

Reperfusion

  • Restoration of blood flow after an ischemic event 
  • Recovery can be achieved (especially with reversible injury).
  • Can paradoxically worsen the injury and lead to cell death → ischemia-reperfusion injury:
    • Reperfusion can exacerbate the damage and injure distant organs when mediators are released into the bloodstream.
    • A clinically significant consideration in the treatment of myocardial infarction and stroke

Mechanism of injury

Perfusion is restored, which brings damaging pathways:

  • Oxidative stress: ↑ production of reactive oxygen species (ROS) or free radicals (molecules with an unpaired electron in the outer orbit):
    • Produced from leukocytes and damaged cells
    • ↑ Due to mitochondrial damage and the inability to reduce oxygen (impaired antioxidant mechanisms from ischemia)
  • Overload of intracellular calcium:
    • ↑ Calcium → opening of mitochondrial permeability transition pore (mPTP) → ATP depletion
    • ↑ Calcium → cellular enzymes (e.g., protease, phospholipase, ATPase, endonuclease) → membrane and nuclear damage
  • Leukocytes and cytokines → recruit more immune cells → ↑ inflammation (“sterile inflammation”)
  • Complement system activation → complement proteins bind ischemic tissues of antibodies → ↑ inflammation

The combination of the mechanisms induce:

  • Damage to DNA, structural proteins, and lipids
  • Further activation of proinflammatory and prothrombotic cascades

Cellular architecture is lost and cell death follows.

Cellular changes and adaptive responses in Ischemic cell damage

Flowchart summarizing the major pathologic events contributing to ischemic (upper panel) and reperfusion (middle panel) components of tissue injury:
In prolonged ischemia, hypoxia leads to depletion of ATP and reduced intracellular pH (from lactate accumulation). ATP-dependent ion transport mechanisms become deranged, causing cellular calcium overload, swelling/rupture, and death.
When oxygen levels are restored (reperfusion), reactive oxygen species (ROS) are generated. Proinflammatory changes also occur: Neutrophils infiltrate ischemic tissues and worsen the ischemic injury. The pathologic events lead to the opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which allow passage of molecules into the mitochondria and further impair ATP production.
PFK: phosphofructokinase

Image by Lecturio.

Clinical Relevance

Ischemic damage

  • Infarct: area of necrotic cells in an organ, arising mainly from hypoxia and ischemia:
    • Red or “hemorrhagic” infarct:
      • Affects organs with multiple blood supplies or loose parenchyma allowing blood to leak into tissue (e.g., lungs)
      • From venous infarcts: The vein is blocked, but the artery delivers blood.
      • Reperfusion injury: The restoration of blood flow causes blood to leak through damaged vessels.
    • Pale/white or “anemic” infarct: injury to organs with a single arterial supply or solid parenchyma (e.g., kidney, heart)
  • Ischemic tolerance time: amount of time to develop irreversible tissue damage after an ischemic injury:
    • Brain:
      • The most susceptible organ to ischemia 
      • The least amount of time before irreversibility occurs
    • Most susceptible organs to reduced blood supply after the brain: The heart/myocardium is the 2nd and the kidneys are the 3rd.
    • Both skin and skeletal muscle tolerate longer periods of ischemia:
      • Often seen in the emergency application of tourniquets (sometimes for hours) with little injury to the tissues
      • Release (after the 1st 2 hours) followed by reapplication of compression produces minimal injuries. 
  • Anatomically, some organs have watershed areas (border zone):
    • The regions have dual blood supply, but are located at the most distal reaches of the arteries.
    • Susceptible to ischemia

Brain

  • With high metabolic activity and low carbohydrate stores, the brain has the highest susceptibility to ischemia.
  • Ischemia occurs when an embolus or thrombus (ischemic stroke) reduces the blood flow:
    • Survival of tissue depends on:
      • Collateral circulation
      • Duration of ischemia
      • Degree and rapidity of blood flow interruption
    • Neurons die within 5 minutes in the case of complete blockage.
  • Watershed areas:
    • The border zones of the arterial territories
    • The area between the anterior and middle cerebral artery distribution is at highest risk.
    • Infarcts develop after significant hypotension.
Watershed areas indicating brain infarct

Watershed areas and infarcts seen on MRI:
a: Watershed areas between the anterior and middle cerebral arterial territories are seen in the anterior blue shade.
Watershed areas between the middle and posterior arterial territories are seen in the posterior blue shade.
b: Occipital watershed infarct is seen at the boundaries of the middle and the posterior arterial territories.

Image: “Watershed territories” by Clothilde Isabel et al. License: CC BY 4.0

Heart

  • In the setting severe ischemia:
    •  Injury to the myocardium is potentially reversible within 30 minutes.
    • Viability progressively decreases after 30 minutes; irreversibility occurs 6–12 hours later. 
  • The most susceptible tissue in the heart is the subendocardial muscle of the left ventricle.
  • Damage from cardiac ischemia leads to:
    • Stable angina: 
      • Angina (chest pain) subsides within 15 minutes of rest or with administration of nitroglycerin. 
      • Derived from a mismatch between myocardial oxygen demand and oxygen supply 
    • Acute coronary syndrome:
      • Unstable or crescendo angina: Angina lasting > 20 minutes at rest or with minimal exertion (troponin levels are normal).
      • Non-ST-elevation myocardial infarction (NSTEMI): 
        • Myocardial infarction with angina and increased troponin
        • Not associated with elevation of the ST segment on ECG
      • STEMI: a myocardial infarction with angina and elevation of the ST segment on ECG

Kidney

  • Vulnerable due to:
    • A significant amount of cardiac output (25%) moving to the kidneys
    • Limited collateral blood supply from extrarenal sites
    • High metabolic activity
  • Shows pale/white infarct when ischemic damage occurs
  • Ischemia can occur in cases of:
    • Hypotension
    • Sepsis
    • Surgery 
  • Interruption to complete obstruction of blood supply noted in:
    • Cardioembolic disease (e.g., atrial fibrillation)
    • Renal artery injury
    • Hypercoagulable state
  • Areas most affected:
    • Proximal tubule (S3 segment): minimal capacity to produce energy in anaerobic conditions
    • The medullary thick ascending limb of the loop of Henle

Liver

  • With a complex vasculature and high metabolic activity, hepatic injury results from severe hypoperfusion.
  • Can occur with an interruption of blood supply to the liver:
    • Hepatic sickle cell crisis 
    • Hepatic artery thrombosis
    • Other systemic conditions (e.g., shock, respiratory failure)
  • Interruption of hepatic blood supply manifests with:
    • Elevation of transaminases 
    • Occasionally with GI symptoms (e.g., nausea, abdominal pain)
  • Often accompanied by other end-organ hypoperfusion (e.g., renal ischemia presenting as ↑ creatinine)
  • Area most affected: zone 3 (area closest to and around the central vein)

Intestine

  • Extensive collateral circulation (protective against hypoperfusion)
  • Even if mesenteric blood flow decreases by 75% for up to 12 hours, injury is minimal due to collateral circulation.
  • Sources of ischemia:
    • Mesenteric arterial occlusion (thrombosis or emboli)
    • Venous thrombosis (↑ resistance from venous flow → bowel edema and ischemia)
    • Nonocclusive mesenteric ischemia (splanchnic hypoperfusion)
  • Watershed areas (large intestine): splenic flexure:
    • Blood supply from the narrow terminal branches of the superior mesenteric artery
    • Griffiths’ point: area of weakness 
  • Rectosigmoid junction:
    • Blood supply from the narrow terminal branches of the inferior mesenteric artery
    • Sudeck’s point: area of weakness

References

  1. El Sabbahy, M., Vaidya, V.S. (2011). Ischemic kidney injury and mechanisms of tissue repair. Wiley interdisciplinary reviews. Systems biology and medicine, 3(5), 606–618. https://doi.org/10.1002/wsbm.133
  2. Friedman, L. (2021). Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy. UpToDate. Retrieved Aug 20, 2021, from https://www.uptodate.com/contents/ischemic-hepatitis-hepatic-infarction-and-ischemic-cholangiopathy#H2
  3. Kalogeris, T., Baines, C.P., Krenz, M., Korthuis, R.J. (2016). Ischemia/Reperfusion. Comprehensive Physiology, 7(1), 113–170. https://doi.org/10.1002/cphy.c160006
  4. Kalogeris, T., Baines, C.P., Krenz, M., Korthuis, R.J. (2012). Cell biology of ischemia/reperfusion injury. International review of cell and molecular biology. 298 : p.229–317. doi: 10.1016/B978-0-12-394309-5.00006-7 
  5. Kemp, W.L., & Burns, D.K., & Brown, T.G. (Eds.), (2008). Chapter 1. cellular pathology. Pathology: The Big Picture. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=499&sectionid=41568284
  6. Lee, J.M., Grabb, M.C., Zipfel, G.J., Choi, D.W. (2000). Brain tissue responses to ischemia. The Journal of clinical investigation, 106(6), 723–731. https://doi.org/10.1172/JCI11003
  7. Mitchell, R., Connolly, A. (2021). The Heart. In Kumar, V., Abbas, A., Aster, J., Robbins, S. (Eds.),Robbins and Cotran Pathologic Basis of Disease (10th ed., pp. 527–555). Elsevier, Inc.
  8. Oakes, S. (2021). Cell injury, cell death and adaptations. In Kumar, V., Abbas, A., Aster, J., Robbins, S. (Eds.),Robbins and Cotran Pathologic Basis of Disease (10th ed., pp. 55–57). Elsevier, Inc.

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